Successful T cell immunotherapeutic strategies are limited by the tolerance to self-antigens, rendering the identification and expansion of tumor-reactive T cells with high avidity for tumor-associated antigens difficult (Mansoor, et al., 2005, Br J Cancer 93: 1085-1091). Further, solid tumors often down-regulate MHC Class I and/or other molecules related with the antigen processing machinery as a mechanism for evading immune response (Han, et al., 2008, Clin Cancer Res 14: 3372-3379). To obviate these obstacles, tumor antigen-specific T cells have been engineered to express chimeric antigen receptors (CAR)—or “T bodies”—comprised of an antigen-specific single-chain antibody fragment (scFv) fused to intracellular signalling domains derived from receptors involved in lymphocyte activation (Gross, et al., 1989, Proc Natl Acad Sci USA 86: 10024-10028). CARs can functionally redirect T cells with high specificity to various surface antigens on tumor cells independent of MHC restriction and antigen processing, and therefore bypass major mechanisms by which tumors escape immune recognition.
CARs targeting various tumor-associated antigens have been developed, characterized and tested (Jena, et al., 2010, Blood 116: 1035-1044). Despite encouraging pre-clinical results, CAR therapy has had limited success in the clinic primarily due to poor long-term persistence of the engineered T cells following infusion to patients. This may be attributed in part to the frequent use of scFvs of mouse origin which renders these constructs susceptible to host immune recognition and responses against xenogeneic regions of the molecule. Xenogeneic responses have been observed in clinical trials of CAR therapy. For example, patients who received autologous T cells transduced to express a CAR of mouse origin mounted humoral immune responses against the transgene bearing cells, which may have limited their persistence in vivo and their ability to respond against antigen-expressing tumor cells (Kershaw, et al., 2006, Clin Cancer Res 12: 6106-6115; Park, et al., 2007, Mol Ther 15: 825-833).
Mesothelin is a glycosylphosphatidyl inositol-linked membrane glycoprotein overexpressed on the cell surface of mesothelioma, ovarian cancer as well as cancers of the pancreas, stomach and lung (Chang, et al., 1996, Proc Natl Acad Sci USA 93: 136-140; Ho, et al., 2007, Clin Cancer Res 13: 1571-1575; Argani, et al., 2001, Clin Cancer Res 7: 3862-3868). Mesothelin also exists as a soluble form and is a serum biomarker for lung, mesothelioma and ovarian cancer (Scholler, et al., 1999, Proc Natl Acad Sci USA 96: 11531-11536; Hassan, et al., 2006, Clin Cancer Res 12: 447-453; Robinson, et al., 2005, Lung Cancer 49 Suppl 1: S109-111). The biological function of mesothelin is still unclear; however mesothelin binds to CA125, a plasma glycoprotein on tumor cells, suggesting that mesothelin may contribute to peritoneal and pleural metastasis (Kaneko, et al., 2009, J Biol Chem 284: 3739-3749; Rump, et al., 2004, J Biol Chem 279: 9190-9198). Mesothelin expression is associated with chemoresistance, shorter disease-free survival and worse overall survival of patients with epithelial ovarian cancer (EOC) (Cheng, et al., 2009, Br J Cancer 100: 1144-1153). Accordingly, mesothelin represents an attractive target for immune-based therapies. While vaccination with granulocyte macrophage-colony stimulating factor-transduced pancreatic cancer lines can induce in vivo mesothelin-specific CD8+ T cells, with the capacity to kill mesothelin-expressing cancer cells in an MHC Class I-restricted fashion (Thomas, et al., 2004, J Exp Med 200: 297-306), more recent work has shown that human T cells bearing an anti-human mesothelin CAR of mouse origin (referred to as SS1) exhibit MHC-independent effector functions in vitro and induce the regression of human mesothelioma xenografts in vivo in immunodeficient mice (Carpenito, et al., 2009, Proc Natl Acad Sci USA 106: 3360-3365).
Thus, there is an urgent need in the art for compositions and methods for treatment of diseases, disorders or conditions associated with dysregulated expression of mesothelin. The present invention addresses this need.